Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Category:

Antiarrhythmic—

cardiotonic—

IndicationsAccepted

Arrhythmias, cardiac (prophylaxis and treatment)—Digitalis glycosides (digitalis) are indicated for the control of ventricular response rates in patients with chronic atrial fibrillation. {01}{53} Digitalis glycosides are also indicated for the control of paroxysmal atrioventricular (AV) nodal reentrant tachycardia; {64} digitalis glycosides may convert paroxysmal AV nodal reentrant tachycardia to normal sinus rhythm. {01}{59}{64}

Congestive heart failure (treatment)—Digitalis glycosides are indicated for the treatment of all degrees of congestive heart failure. Their positive inotropic action results in improved cardiac output and an improvement in the signs and symptoms of hemodynamic insufficiency such as dyspnea, edema, and/or venous congestion.
— Although digoxin has been shown to improve symptoms of heart failure, it does not prolong life, as was determined in a large, randomized, double-blind trial known as the Digitalis Investigation Group (DIG) study {124}. In this trial, the effect of digoxin on mortality and morbidity was evaluated in patients with heart failure {124}. It was concluded that digoxin did not reduce overall mortality, but that it did reduce the rate of hospitalization for worsening heart failure {124}.Unaccepted
The use of digitalis glycosides in the treatment of obesity has been determined unwarranted and dangerous, since these drugs may cause potentially fatal arrhythmias or other adverse effects {01}.

Two major actions are produced by therapeutic doses of digitalis glycosides:

(1) Force and velocity of myocardial contraction are increased (positive inotropic effect). This effect is thought to result from inhibition of movement of sodium and potassium ions across myocardial cell membranes by complexing with adenosine triphosphatase. As a result, there is enhancement of calcium influx and an augmented release of free calcium ions within the myocardial cells to subsequently potentiate the activity of the contractile muscle fibers of the heart.

(2) A decrease in the conduction rate and increase in the effective refractory period of the atrioventricular (AV) node is due predominantly to an indirect effect resulting from enhancement of parasympathetic tone and possibly from a decrease in sympathetic tone (the occurrence of the latter effect is controversial) {127}{128}{129}.

Digitalis glycosides differ predominantly in their pharmacokinetic properties, as opposed to their pharmacodynamic properties {73}.

Digoxin—Absorption occurs by passive diffusion {01} in the proximal part of the small intestine {87}. Bioavailability is 60 to 80% (tablets), 70 to 85% (oral elixir), or 90 to 100% (capsules) {01}. The rate, but not the extent, of oral absorption is reduced when the tablets are taken after meals {01}.Distribution:

Digoxin—Apparent Vol D: 6 to 8 L/kg {73}{87}; digoxin concentrates in tissues, with a distribution space that correlates with lean body weight as opposed to total body weight {87}. Digoxin is distributed into cerebrospinal fluid, although to a lesser degree than into other tissues {87}.Protein binding:

Digitoxin—Metabolism occurs in the liver and produces several metabolites {60}. The only active metabolite is digoxin, which makes up a small fraction of the total metabolites of digitoxin {60}.

Digoxin—Metabolism occurs partially in the stomach, but also may occur in the liver {90} and, although only about 16% of a dose of digoxin is metabolized {01}, several metabolites of digoxin and their metabolic pathways have been identified {90}. The bis-digitoxoside and mono-digitoxoside metabolites are considered to be cardioactive {90}. Other metabolites, such as digoxigenin, are considered to be less cardioactive than digoxin {90}. In some patients (estimated to be approximately 10% of patients taking digoxin {72}), other cardioinactive metabolites, such as dihydrodigoxin and dihydrodigoxigenin, may result from the metabolism of digoxin by intestinal bacteria {23}{62}{90}. In these individuals, as much as 40% or more of an oral dose of digoxin may be converted to these inactive reduction products {01}.Half-life:

Digoxin—0.8 to 2 nanograms/mL; however, interindividual variability can be substantial and a patient can show signs of toxicity even though serum concentrations are within this range {01}. Infants and children may tolerate higher peak serum digoxin concentrations than do adults {01}{125}.Elimination:
Digitoxin—Primarily hepatic (biliary/fecal), but also renal {86}. Elimination is independent of renal function {60}{89}.
Digoxin—Primarily renal (50 to 70% of an intravenous dose may be recovered unchanged in the urine) {01}, but also hepatic (biliary) {87}; digoxin may accumulate in patients with renal function impairment {01}.

In dialysis—
Digitoxin: Not expected to be removed by hemodialysis because digitoxin is extensively bound to plasma protein {86}.
Digoxin: Not effectively removed by dialysis or exchange transfusion because most of the drug is in the tissue instead of the blood {01}.

Pregnancy—
Appropriate and well-controlled studies have not been done in pregnant women {01}. Use of digitalis glycosides in pregnant women is not recommended unless absolutely needed {01}{60}.

FDA Pregnancy Category C.

Postpartum —
Following delivery, and for up to 6 weeks thereafter, the maternal dosage often must be reduced to maintain acceptable serum concentrations.Breast-feeding

Digoxin is distributed into breast milk, reaching concentrations similar to those in serum {01}. Although the total amount received daily by the infant has been estimated to be less than the usual maintenance dose for an infant, caution should be used {01}. It is not known whether digitoxin is distributed into breast milk {60}.Pediatrics

Digitalis glycosides are a major cause of poisoning in children {01}. The tolerance of newborn infants to digitalis glycosides is variable, {01} since their renal clearance of the medication is reduced. Premature and immature infants are especially sensitive {01}. Dosage should be reduced and individualized according to the infant's degree of maturity {01}, since renal clearance increases as the infant matures {04}{05}{06}{07}{08}{09}. Children older than l month of age generally require proportionally larger doses than adults on the basis of body weight or body surface area {05}{13}{14}{15}{16}.

Geriatrics

Although appropriate studies on the relationship of age to the effects of digitalis glycosides have not been performed in the geriatric population, the majority of experience with digoxin is in this population {01}. Elderly patients may be more likely to have age-related renal function impairment, which may significantly increase the elimination half-life of digoxin {73}. Additionally, elderly patients may have a decreased volume of distribution of digitalis due to decreased muscle mass {60}{73}. These factors may contribute to digitalis toxicity in elderly patients {73}.Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Digitalis glycosides have a narrow therapeutic range and changes in digitalis pharmacokinetics and/or pharmacodynamics caused by a digitalis-drug interaction can result in toxicity or underdigitalization {74}. The presence of or a change in an underlying disease state also can cause changes in digitalis pharmacokinetics and/or pharmacodynamics and may complicate or contribute to a digitalis-drug interaction {73}{74}{131}. Although there are several consistent, well-known, digitalis-drug interactions {74}, numerous studies, reports, opinions, and conclusions about digitalis-drug interactions disagree on the existence or clinical significance of a number of interactions {130}. Because a risk of digitalis toxicity exists {73}, and the clinical significance of an interaction may be variable and not necessarily predictable {73}{74}{130}, it is important that the addition or withdrawal of a drug to or from a therapeutic regimen that includes digitalis be carefully evaluated in the context of the patient and the clinical situation {74}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Albuterol{91}{92} (concurrent use may decrease serum digoxin concentrations {91}, possibly by redistributing digoxin to other tissues {92}; albuterol may also decrease serum potassium concentrations, which may increase the risk of digoxin toxicity {92})

Alprazolam{18}{19}{20} (concurrent use may increase serum digoxin concentrations, possibly by decreasing the renal clearance of digoxin {19}; although one small study performed in healthy volunteers concluded that alprazolam had no significant effect on digoxin clearance {18}, contradictory evidence has been reported in patients [primarily elderly patients] receiving long-term digoxin therapy {19}{20})

» Amiodarone{01}{36}{38} (increases in serum digoxin concentrations by as much as 100% have been reported with concurrent use {74}. Although it is thought that amiodarone decreases renal and/or nonrenal clearance and/or the volume of distribution of digoxin, other contributing factors, such as amiodarone-induced displacement of digoxin from tissue binding sites {112}, also may be involved {115}. Amiodarone has a long elimination half-life [15 to 65 days or longer] {112} and digoxin toxicity may not appear until several weeks after the addition of amiodarone {38}{112} or may persist long after discontinuation of amiodarone {115})

Antacids{01} or
Antidiarrheal adsorbents (e.g., kaolin and pectin){01} or
Sulfasalazine{01} (concurrent use may decrease digoxin bioavailability by decreasing digoxin absorption. In the case of antidiarrheal adsorbents and sulfasalazine, the digoxin dose may be administered 8 hours before the interacting medication {84})

Antibiotics, oral, especially
Macrolide antibiotics{01} , such as:
Clarithromycin{01} or
Erythromycin{01}{33}{58}{72}{62} or
Tetracycline{01}{72} (concurrent use of some oral antibiotics may increase serum digoxin concentrations in patients who inactivate digoxin in the lower intestine by bacterial metabolism {01}; in these individuals, altering the bowel flora with certain antibiotics may diminish digoxin conversion to inactive metabolites, resulting in increased serum digoxin concentration; the increase in serum digoxin concentration has been as much as twofold in some cases and correlates with the extent of bacterial inactivation {01}. Although there are limited data, this interaction has been reported with oral use of clarithromycin, erythromycin, and tetracycline {01}{33}{58}{62}{72}{100}{101}{102})

Anticancer medications{01} (such as bleomycin, cyclophosphamide, cytarabine, doxorubicin, procarbazine, and vincristine{74} ) or
Radiation therapy{35}{74} (concurrent use may decrease digoxin bioavailability by decreasing digoxin absorption; the reduced absorption that occurs during concurrent use with anticancer medications or radiation therapy may be due to temporary damage to the gastrointestinal mucosa and may continue for several days after treatment {74}; in these patients, a dosage form with greater bioavailability, such as the capsule or solution, may help to minimize decreased bioavailability {35}{74}{98}{99}; digitoxin absorption does not appear to be affected by anticancer agents {74})

Atorvastatin{69} (concurrent use may increase digoxin serum concentrations; steady-state serum concentration increases of approximately 20% have been reported {69})

» Beta-adrenergic blocking agents{01} , including
Atenolol
Carvedilol{95}
Metoprolol and
Propranolol (concurrent use with these agents may have additive effects on slowing atrioventricular [AV] nodal conduction {01}; concurrent use with carvedilol in patients with hypertension increased the steady-state area under the plasma concentration–time curve [AUC] and trough concentrations of digoxin by 14% and 16%, respectively {95}; monitoring of plasma digoxin concentrations is recommended {95})

Bran fiber, dietary{30}{31}{104}{105} (it is uncertain whether concurrent administration of dietary bran fiber decreases digoxin bioavailability. In one small study, there was presumed to be a decrease in digoxin absorption when concurrent administration of digoxin with 5 grams of fiber resulted in a decrease in urinary excretion of digoxin. Another small study found no change in steady-state serum digoxin concentrations when digoxin was administered 15 to 30 minutes before administration of 11 grams of bran [as a bran muffin], with a second bran muffin administered several hours later {30}{31}{104}{105})

» Calcium channel blocking agents{01} , especially
Bepridil{75} or
Diltiazem{79}{80} or
Nifedipine{78} or» Verapamil{01}{74} (concurrent use with calcium channel blocking agents may have additive effects on AV nodal conduction, which could result in complete heart block {01}; concurrent use also may increase serum digoxin concentrations by reducing digoxin renal clearance, possibly as a result of inhibition of active tubular secretion of digoxin {79}{81}; verapamil may increase serum digoxin concentrations by 30 to 200% {74}; bepridil may increase serum digoxin concentrations by approximately 34% {75}; some studies have reported no interaction with diltiazem while others have reported increases in serum digoxin concentrations of 20 to 60% {74}{79}{80}; contradictory evidence of an interaction also exists for nifedipine, although serum digoxin increases of 15 to 50% have been reported {74}{77}{78}; increases in serum digitoxin concentrations also have been reported with concurrent use of diltiazem and verapamil, although increases were less pronounced than with digoxin use and may be due to a reduction in extrarenal digitoxin clearance {81}; serum digitalis concentrations and electrocardiogram [ECG] should be monitored and dosages adjusted accordingly {22})

Cholestyramine{01}{104} or
Colestipol{74} (colestipol and cholestyramine may delay and reduce the absorption of digoxin {106}; the digoxin dose may be administered 8 hours before the interacting medication to minimize the interference with digoxin absorption {84}{104})

Cyclosporine{93}{94}{118} (concurrent use has resulted in increases in serum digoxin concentrations, possibly as a result of decreased apparent volume of distribution and/or plasma clearance of digoxin {93}{94}{118})

Flecainide{82}{83} (concurrent use has increased serum digoxin concentrations, on average, by 24% {82}{84}; it also has been speculated that concurrent use may cause a slight additive increase in the PR interval {82}{84})

Hepatic enzyme inducers{60} (see Appendix II ) such as:
Barbiturates{60} or
Phenytoin{60} or
Rifampin{85} (concurrent use may increase the metabolism of digitoxin {60}; serum digitoxin concentrations have been reported to decrease by 50% in patients who received 180 mg of phenobarbital per day for 12 weeks {60}; decreases in serum digoxin concentrations also have been reported with concurrent use of rifampin, although the mechanism for this interaction is not completely understood {85}; serum digitalis concentrations should be monitored and dosages adjusted accordingly {85})

Indomethacin{01}{38} (concurrent use may increase digoxin serum concentrations, possibly by inhibiting the renal elimination of digoxin {38}; two small studies that evaluated the interaction in healthy adult patients did not find a clinically significant interaction {108}{111}. Another small study found a significant increase [about 40% on average] in serum digoxin concentrations in adult heart failure patients treated with digoxin on a long-term basis {109}. A small study in premature infants treated conventionally with indomethacin for patent ductus arteriosus [PDA] found an increase in serum digoxin concentrations of approximately 50% with concurrent use {110})

Metoclopramide{98} (concurrent use of metoclopramide may decrease digoxin absorption by increasing gastrointestinal motility {98}; serum digoxin concentrations as determined by AUC have been reported to decrease by about 24% {98})

Neomycin{01}{117} , oral (concurrent use decreases the rate and extent of absorption of digoxin {117}. In a study in healthy volunteers, the extent of absorption of digoxin was decreased by as much as 51% after single doses of digoxin and neomycin {117}. The absorption of digoxin also was decreased when the antibiotic was given 3 or 6 hours before the digoxin dose {117}. The mechanism of this interaction has not been established {117}, but it is recommended that digoxin be administered at least 8 hours before neomycin {84})

Omeprazole{96}{97} (concurrent use with digoxin may increase digoxin absorption, possibly by altering gastric acidity; on average, C max and AUC values have been reported to be about 10% higher with concurrent use {97})

» Propafenone{01}{54}{55}{56}{57} (concurrent use of propafenone with digoxin results in an increase in serum digoxin concentrations ranging from 35 to 85%, which appears to be unrelated to digoxin renal clearance but may be related to a decrease in the volume of distribution and nonrenal clearance of digoxin {56}; careful monitoring of digoxin concentrations {55} and dosage reduction of digoxin are recommended when propafenone is initiated {84})

» Quinidine{01} or
Quinine{74}{84} (concurrent use with quinidine has resulted in increased digoxin plasma concentrations, possibly due to an initial displacement of digoxin from quinidine binding sites {84}, and a reduction in the renal and nonrenal clearance and volume of distribution of digoxin {39}{40}; the extent of the interaction is proportional to plasma quinidine concentrations and, on average, concurrent use results in 100% increases in serum digoxin concentrations, although increases of over 300% have been reported {39}{40}; concurrent use of quinidine with digitoxin has resulted in increases in serum digitoxin concentrations of 30 to 67%, the smaller increases possibly resulting from impairment of extrarenal clearance of digitoxin by quinidine {24}; increases in serum digoxin concentrations also have been reported with concurrent use of quinine {84}; serum digitalis concentrations should be monitored and dosage adjusted as indicated)

Spironolactone{25}{26} (concurrent use with digoxin may increase serum digoxin concentrations, possibly by decreasing digoxin renal and nonrenal clearance and/or digoxin volume of distribution {25}{26}; it has been estimated that digoxin plasma concentrations may increase by one third with concurrent use {26})

Succinylcholine{01} (concurrent use may cause a sudden release of potassium from muscle cells, increasing the risk of arrhythmias in digitalized patients {01})

Sucralfate{42} (sucralfate was reported to reduce digoxin plasma concentrations by about 19%, presumably by reducing the bioavailability of digoxin {42}. Sucralfate should not be taken within 2 hours of digoxin {41})

» Sympathomimetics{01}{74} (concurrent use may increase the risk of cardiac arrhythmias {01})

Thyroid hormones{01} (patients with thyroid disease may have an altered sensitivity to digitalis: hyperthyroid patients may have a reduced response to digitalis and hypothyroid patients may have an increased risk of digitalis toxicity {126}; use of thyroid hormones in a hypothyroid patient who has been digitalized may require an increase in the digitalis dose {01})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Digoxin, serum{28}{34}{44}{45}{46}{47}{48}{49}{113} (false-positive increases in serum digoxin concentrations have occurred from the presence of a digoxin-like immunoreactive substance in patients with hepatic or renal function impairment, in pregnant women, in patients with hypertension, in infants and neonates, and in patients with chronic heart failure {28}{34}{44}{45}{46}{47}{48}{49}. In patients treated with digoxin-immune Fab antibody fragments, serum digoxin concentrations may increase 5 to 20 times as a result of inactive intravascular concentrations of Fab-bound digitalis complexes {113}{125})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, these medications should not be used when the following medical problems exist:» Hypersensitivity to digoxin or digitoxin{01}» Ventricular fibrillation{01}Risk-benefit should be considered when the following medical problems exist» Cardiomyopathy, hypertrophic, with left ventricular outflow obstruction (idiopathic hypertrophic subaortic stenosis){01} or» Cor pulmonale, acute{01} or» Heart failure associated with diastolic dysfunction{01} , such as
Cardiomyopathy, restrictive, as associated with
Amyloid cardiomyopathy{01} or
Pericarditis, constrictive{01} (these conditions may be particularly sensitive to the inotropic effects of digitalis or may worsen with digitalis administration {01})

» Atrioventricular (AV) accessory pathway accompanied by atrial flutter or fibrillation (Wolff-Parkinson-White syndrome){01} (patients receiving intravenous digoxin have developed a rapid ventricular response or ventricular fibrillation as a result of an increase in antegrade conduction over the accessory pathway, bypassing the AV node {01}. Digitalis should not be used in these patients unless accessory pathway conduction has been surgically blocked or pharmacologically depressed {01})

» AV block, without a functioning cardiac pacemaker{01} or» Sinus node dysfunction, without a functioning cardiac pacemaker{01} (because digitalis slows sinoatrial [SA] and AV conduction and prolongs the PR interval, administration of digitalis in patients with sinus node dysfunction can result in severe sinus bradycardia or SA block; similarly, administration of digitalis in patients with incomplete AV block can result in advanced or complete AV block {01})

Arteriovenous shunt{01} or
Hypoxia{01} or
Thyroid disease{01} (use of digitalis for the treatment of heart failure and/or atrial arrhythmias associated with these disease states may predispose the patient to toxicity once the primary disorder is corrected {01}; patients with hypothyroidism may have reduced requirements for digitalis and, contrarily, patients with hyperthyroidism may be resistant to treatment with digitalis {01})

Electrical cardioversion{01} (conventionally, regardless of the serum concentration of digitalis, the dose of digitalis was reduced or withheld 1 to 2 days prior to cardioversion of atrial fibrillation because it was thought that the use of digitalis during electrical cardioversion would provoke ventricular arrhythmias {01}{119}. Although electrical cardioversion in patients with digitalis toxicity has been shown to provoke ventricular arrhythmias, a study in patients with clinically therapeutic digitalis serum concentrations [nontoxic concentrations] determined that these patients may safely undergo electrical cardioversion without reducing or withholding the dose of digitalis [and without the concurrent use of an antiarrhythmic agent] {119}. It also should be taken into consideration that serum digitalis concentrations are not the only determining risk factor for development of ventricular arrhythmias postcardioversion {120}. If digitalis toxicity is suspected, cardioversion should be postponed {01})

» Electrolyte disorders (resulting from dialysis, diarrhea, diuretics or other medications, malnutrition, prolonged vomiting, etc.){01} , especially {01}» Hypercalcemia{01}» Hypocalcemia{01}» Hypokalemia{01} and» Hypomagnesemia{01} (hypokalemia and hypomagnesemia cause the myocardium to be sensitive to digoxin and toxicity may occur {01}; hypercalcemia has an additive effect on the contractility and excitability of the heart and may increase the risk of digitalis toxicity {01}; if intravenous calcium salts are administered rapidly to a digitalized patient, serious arrhythmias may occur {01}; conversely, hypocalcemia can counteract the effects of digoxin on the heart {01})

Hepatic function impairment{60} (the dose of digitoxin may need to be reduced in these patients {60})

Myocardial infarction, acute{01} (the use of inotropic agents, such as digitalis, may increase myocardial oxygen demand and cause ischemia in some of these patients {01}; digitalis should be used with caution in these patients {01})

» Renal function impairment{01} (because digoxin is eliminated predominantly by the kidneys, the elimination half-life of digoxin may be prolonged when renal function is impaired, increasing the time to reach a steady-state serum concentration {01}; these patients may be more likely to experience digoxin toxicity and to have toxic effects of longer duration {01}; the dose of digoxin should be reduced in these patients {01})

Patient monitoringThe following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Cardioglycoside, steady-state, trough serum concentrations{51}{52} (it is recommended that concentrations be obtained at initiation of therapy and periodically thereafter, unless a change occurs in the patient's clinical status, in which case, more frequent monitoring may be necessary {28}. Other factors that may indicate a need for monitoring are: a change in renal function, lack of a response to the digitalis glycoside, decompensated heart failure, addition of an interacting medication, suspected digoxin toxicity, or assessment of compliance {28}. To allow adequate distribution of digoxin, sampling should be done just before the next scheduled dose or, if that is not possible, at least 6 to 8 hours after the last dose, regardless of the route of administration or formulation used {01}; serum concentrations always should be interpreted in the overall clinical context and should not be used as a basis for changing the dosage {01}. Furthermore, in patients with atrial fibrillation, serum concentrations are less important than the clinical response; if the heart rate is controlled and the patient is without signs of toxicity, serum concentrations should not be obtained nor the dosage changed {114}. If a discrepancy exists between the reported serum concentration and the observed clinical response, the following reasons might be considered: analytical problems in the assay procedure, an inappropriate serum sampling time, administration of a digitalis glycoside other than what was prescribed, occurrence of a physiological condition that has altered the patient's sensitivity to digitalis, or an abnormal patient response to digitalis {01})

» Electrocardiogram (ECG) monitoring (recommended at periodic intervals; if paroxysmal atrial tachycardias with atrioventricular (AV) block {50} or ventricular tachycardia occurs, withholding the digitalis glycoside should be considered until serum digoxin concentration and electrolyte status are evaluated. Clinical judgment is essential since withholding of digitalis also may have adverse consequences {114})

» Electrolyte, especially potassium, calcium, and magnesium{27} concentrations, serum (recommended at periodic intervals, especially in patients also receiving diuretics, to detect possible electrolyte imbalance, which may increase the chance of digitalis toxicity, particularly with regard to arrhythmias, and may affect dosage requirements)

Pulse (apical) check (recommended at periodic intervals, especially in patients with atrial fibrillation or when a dosage change is made)

Side/Adverse Effects

Note: Digitalis side/adverse effects are dose-related and usually occur at doses higher than those needed for a therapeutic effect {01}. Some patients may be particularly sensitive to some side/adverse effects of digitalis and may manifest symptoms of toxicity even though serum digitalis concentrations are within the therapeutic range {01}{28}. Physiological changes associated with aging, underlying illnesses, and concurrent use of other medications (diuretics) also can affect the occurrence of digitalis side/adverse effects and/or toxicity {28}{73}. Additionally, children may experience different side/adverse/toxic effects than adults {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:Those indicating need for medical attentionIn adultsWith therapeutic, high, or toxic dosesCardiovascular effects, such as atrial tachycardia with block{01}atrioventricular (AV) dissociation{01}heart block, first-, second-, or third-degree{01}junctional (nodal) rhythm, accelerated{01}PR interval prolongation{01}ST segment depression{125}ventricular fibrillation{01}ventricular premature contractions, unifocal or multiform (especially bigeminy or trigeminy){01}and ventricular tachycardia{01} (cardiovascular effects may be manifested as slow and/or irregular heartbeat, palpitations, or fainting)central nervous system (CNS) effects, such as anxiety{01}apathy{01} (feeling of not caring), blurred or yellow vision{01}confusion{01}dizziness{01}hallucinations{01} (seeing or hearing things that are not there), headache{01}mental depression{01}and weakness{01}gastrointestinal effects, such as abdominal pain{01}anorexia (loss of appetite), diarrhea{01}nausea{01}and vomiting{01}Incidence rareSkin rash{01}thrombocytopenia{01} (may be seen as nosebleeds or bleeding gums)With long-term useGynecomastia{01} (enlargement of breast tissue in males)

Note: The earliest and most frequently encountered side effects that are associated with excessive dosing in infants and children are cardiac arrhythmias, especially conduction disturbances and supraventricular tachycardias ( atrial tachycardia [with or without block] and junctional [nodal] tachycardia) {01}.

Incidence less frequentCNS effects, such as anxiety{01}apathy{01}blurred or yellow vision{01}confusion{01}dizziness{01}hallucinations{01}headache{01}mental depression{01}weakness{01}gastrointestinal effects, such as anorexia{01}diarrhea{01}nausea{01}vomiting{01}

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).Clinical effects of overdose
The clinical effects of digitalis overdosage cannot be differentiated significantly from those of toxicity at therapeutic or high doses (see Side/Adverse Effects section), except in cases of massive overdose {73}.

Clinical effects of massive overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:Acute and/or chronic in adultsBradyarrhythmias, progressive {01}cardiac arrestheart block {01}ventricular fibrillation {01}ventricular tachycardia {01}

Treatment of overdose

Note: Previous adjunctive treatments in the management of non–life-threatening digitalis intoxication, such as repetitive doses of activated charcoal, cholestyramine, and/or colestipol (presumably to interrupt the enterohepatic recycling of digoxin to enhance elimination), have not been shown to be clinically effective {125}. Previous strategies for treatment of hyperkalemia (insulin, sodium bicarbonate, and/or sodium polystyrene sulfonate) and ventricular arrhythmias (antiarrhythmic agents such as amiodarone, bretylium, lidocaine, phenytoin, propranolol, verapamil, and other drugs) have been replaced by more clinically safe and effective treatment with Fab antibody fragments {125}.

Subtle signs or symptoms of digitalis toxicity should be managed by a dosage reduction or withdrawal of digitalis or by identifying and correcting other factors that contribute to toxic effects (such as electrolyte disturbances or drug interactions) {01}{73}. Asymptomatic bradycardia or atrioventricular (AV) block may require only temporary withdrawal of the drug and cardiac monitoring {01}.

For hypokalemia: In cases of low or normal serum potassium concentrations, administration of potassium may help to antagonize the digitalis toxic effects {73}; however, because severe digitalis intoxication can cause a redistribution of potassium from inside to outside the cell, resulting in hyperkalemia, administration of potassium may be dangerous in cases of massive overdose {01}.

For hyperkalemia: In cases of high serum potassium concentrations, further increases in serum potassium may result in complete AV block or cardiac arrest {73}. If potassium concentrations exceed 5 mEq per L, digoxin immune Fab should be used {88}.

For massive (acute) overdoses:
To decrease absorption: Emesis generally is not recommended except prior to presentation at the hospital. Gastric lavage may be used only if ingestion occurred within 1 hour {122}, but should not be used in patients who are obtunded or exhibit toxic symptoms {01}{73}. Emesis or gastric lavage also is not recommended in patients with underlying heart disease or arrhythmias because it may provoke arrhythmias by augmenting vagal tone {73}.

Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Digitalis Medicines (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):Before using this medication» Conditions affecting use, especially:Hypersensitivity to digitoxin or digoxin

Pregnancy—Digoxin crosses the placenta and should not be used in pregnant women unless absolutely needed; it is not known if digitoxin crosses the placenta

Breast-feeding—Digoxin is distributed into breast milk; caution should be used. It is not known whether digitoxin is distributed into breast milk

Use in children—Infant responses vary; careful dosage adjustment is required

Use in the elderly—Elderly patients may be at greater risk of toxicityOther medications, especially amiodarone; beta-adrenergic blocking agents, including atenolol, carvedilol, metoprolol, and propranolol; calcium channel blocking agents, especially verapamil; potassium-depleting diuretics; propafenone; quinidine; or sympathomimeticsOther medical problems, especially acute cor pulmonale; atrioventricular (AV) accessory pathway (Wolff-Parkinson-White syndrome) accompanied by atrial flutter or fibrillation; AV block, without a functioning cardiac pacemaker; electrolyte disorders; heart failure associated with diastolic dysfunction; hypertrophic cardiomyopathy with left ventricular outflow obstruction; renal function impairment; sinus node dysfunction, without a functioning cardiac pacemaker; or ventricular fibrillationProper use of this medication» Compliance with therapy; taking exactly as directed, not taking more or less medication than the dosage prescribed; taking medication at the same time each day to maintain the therapeutic effect

Proper administration of elixir: Taking orally; special dropper to be used for accurate measuring

» Proper dosing
Missed dose: Taking as soon as remembered if within 12 hours of scheduled dose {27}; not taking if remembered later; not doubling doses; checking with doctor if dose missed for 2 days or more

» Proper storagePrecautions while using this medication
Seeing the physician regularly to check progress

» Checking with physician before discontinuing medication

» Keeping medication out of reach of children

» Reporting to physician any nausea, vomiting, diarrhea, loss of appetite, irregular or slow pulse, palpitations, and/or fainting as possible signs of overdose; initial overdose signs may occur as gastrointestinal effects in adults and as cardiovascular effects in children

General Dosing Information
Recommended doses are averages only; each dose must be adjusted to meet the individual patient's requirements.

Reduction of digitalis glycoside dosage prior to cardioversion may be desirable; however, the benefit must be weighed against the risk of a rapid increase in ventricular response to atrial fibrillation if the digitalis glycoside is withheld 1 to 2 days prior to cardioversion {01}. If digitalis glycoside toxicity is suspected, electrical cardioversion of arrhythmias should be delayed.

Precautions:
Medical considerations/contraindications—Dosage reduction not necessary in renal function impairment; however, a dosage adjustment may be necessary in patients with hepatic function impairment.

Digitalization:
Rapid—Oral, 600 mcg (0.6 mg) initially, then 400 mcg (0.4 mg) after four to six hours and 200 mcg (0.2 mg) after another four- to six-hour period, followed by a daily maintenance dose as needed and tolerated, or {60}

Slow—Oral, 200 mcg (0.2 mg) two times a day for four days, followed by a daily maintenance dose as needed and tolerated. {02}{60}

Maintenance:
Oral, 50 to 300 mcg (0.05 to 0.3 mg) once a day, the dosage being adjusted as needed and tolerated. {60}

Usual adult prescribing limits
Digitalization—A total of 1.6 mg over one or two days.Usual pediatric dose
Prepared oral digitoxin dosage forms are limited and may not be suitable for small children.Strength(s) usually available
U.S.—
Not commercially available.

Canada—

100 mcg (0.1 mg) (Rx) [Digitaline]Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.Auxiliary labeling:
• Keep out of reach of children.
• Do not take other medicines without advice from your doctor.

Precautions:
Medical considerations/contraindications—Dosage reduction may be required in patients with renal function impairment.

Additional Dosing Information

Note: Patient response and sensitivity to digoxin can vary substantially and dosages may require considerable modification {01}. Doses of digoxin should be based upon lean body weight and should be adjusted according to the patient's renal function (based on creatinine clearance), age, underlying illnesses, concurrent medications, and/or other factors that may alter the pharmacokinetics or pharmacodynamics of digoxin {01}. A variety of equations, algorithms, dosing charts, nomograms, and recommendations exist for determining both the loading and maintenance doses of digoxin. The recommended dosages that appear in this text are based upon the manufacturer's product information. For dosing information in chart form, based on corrected creatinine clearance and lean body weight, see the manufacturer's product information.

Bioequivalence information
Bioavailability differences exist among dosage forms of digoxin. Changing therapy from one dosage form to another may require dosage adjustments.

Absolute bioavailability of digoxin is as follows: Tablets—60 to 80%; elixir—70 to 85%; liquid-filled capsules—90 to 100%; and intravenous injection—100% {01}.

For digoxin tablets
Variability in the bioavailability of digoxin tablets was recognized as a clinical problem in the early 1970s. {66}{67}{68} These differences in bioavailability were reported among different brands of digoxin tablets as well as among different lots of digoxin tablets produced by the same manufacturer. {68} In response to the problems of bio-inequivalence, official dissolution standards were established. {68} Problems have not been reported following establishment of these standards. However, because bioavailability from any digoxin tablet is incomplete (£ 80%), clinicians should consider this as a possible source of the problem when unexplained difficulty is encountered in the digitalization or maintenance therapy of patients with digoxin tablets.

Oral Dosage FormsDIGOXIN CAPSULES

Note: Digoxin capsules (digoxin solution in capsules) have an absolute bioavailability close to that of the intravenous injection dosage form {61}. However, the capsules have a greater bioavailability than the tablets or elixir because they are more completely absorbed {61}. The recommended oral dose of digoxin capsules is 80% of that for the tablets or elixir {61}. See Bioequivalence information section.

Usual adult dose
Congestive heart failure

Digitalization:
Rapid digitalization is achieved by administering a loading dose based upon projected peak digoxin body stores (body stores of 8 to 12 mcg per kg of body weight in patients with heart failure and normal sinus rhythm; body stores of 6 to 10 mcg per kg of body weight for heart failure patients with renal insufficiency) {61}. Roughly one half the total loading dose is given as the first dose, with the remaining portion divided and administered every six to eight hours (e.g., 400 to 600 mcg [0.4 to 0.6 mg] initially, followed by 100 to 300 mcg [0.1 to 0.3 mg] administered every six to eight hours) until an appropriate clinical response is achieved {61}. Before each additional dose is given, the patient's clinical response should be assessed carefully {61}. If the patient's clinical response requires a change from the calculated loading dose of digoxin, calculation of the maintenance dose should be based upon the amount actually given {61}. For a 70-kg patient to achieve peak body stores of 8 to 12 mcg per kg of body weight, the usual amount administered is 600 to 1000 mcg (0.6 to 1 mg) {61}.

Slow digitalization is achieved by beginning an appropriate maintenance dose (allowing digoxin body stores to accumulate slowly) {61}. Steady-state serum digoxin concentrations will be achieved in approximately five half-lives {61}. Depending upon the patient's renal function, digitalization by this method will take between one and three weeks {61}.

Maintenance:

Digoxin maintenance doses for estimated peak body stores of 10 mcg per kg of body weight generally have ranged from 50 to 350 mcg (0.05 to 0.35 mg), administered orally as one or two doses per day, the dosage titrated according to the patient's age, lean body weight, and renal function {61}. In patients digitalized with a loading dose, the subsequent maintenance dose can be calculated as a percentage of the loading dose {61}. Doses may be increased every two weeks according to clinical response {61}.

Atrial fibrillation, chronic
Doses should be titrated to the minimum dose that achieves the desired ventricular rate control without causing undesirable side effects {61}.

Usual pediatric dose
Congestive heart failure
Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area {61}. Children older than 10 years of age require adult dosages in proportion to their body weight {61}. Some researchers have suggested that infants and young children tolerate slightly higher serum digoxin concentrations than do adults {61}. For digitalization and maintenance dosing of children younger than 2 years of age, see Digoxin Elixir USP or Digoxin Injection USP . The following digitalizing and maintenance doses are based on lean body weight for children with heart failure and normal renal function {61}:

Digitalizing dose:
Digitalizing doses for the capsules are the same as intravenous digitalizing doses {61}. The following total amounts should be divided into three or more doses, with the initial portion representing approximately one half the total, and the remaining doses administered every six to eight hours, with careful assessment of clinical response before each additional dose {61}. If the patient's clinical response requires a change from the calculated loading dose of digoxin, the calculation of the maintenance dose should be based upon the amount actually given {61}.

Children 2 to 5 years of age—
Oral, 25 to 35 mcg (0.025 to 0.035 mg) per kg of body weight {61}.

Children 5 to 10 years of age—
Oral, 15 to 30 mcg (0.015 to 0.030 mg) per kg of body weight {61}.

Children 10 years of age and older—
Oral, 8 to 12 mcg (0.008 to 0.012 mg) per kg of body weight {61}.

Maintenance dose:

Note: Divided daily dosing is recommended for infants and children up to 10 years of age {61}.

Children 2 years of age and older—
Oral, 25 to 35% of the oral or intravenous total digitalizing dose, based on desired clinical response {61}.

Canada—
Not commercially available.Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F). Store in a tight container and protect from light {01}.Auxiliary labeling:
• Keep out of reach of children.
• Keep container tightly closed.
• Do not take other medicines without advice from your doctor.

DIGOXIN ELIXIR USP

Note: Digoxin elixir and tablets are similar in bioavailability but are less bioavailable than the capsule or intravenous injection dosage forms {133}. When switching from the intravenous injection dosage form to the less bioavailable oral elixir dosage form, the recommended dose of the oral elixir is 1.25 times the intravenous dose (e.g., 100 mcg of digoxin injection is considered equivalent to 125 mcg of the elixir) {133}. See Bioequivalence information section.

Usual pediatric dose
Congestive heart failure
In newborns, digoxin renal clearance is diminished (especially in premature infants) and digoxin doses should be adjusted accordingly {133}. Beyond the immediate newborn period, children generally require proportionally larger doses than do adults, on the basis of body weight or body surface area {133}. Children older than 10 years of age require adult dosages in proportion to their body weight {133}. Some researchers have suggested that infants and young children tolerate slightly higher serum digoxin concentrations than do adults {133}. The following digitalizing and maintenance doses are based on lean body weight for children with heart failure and normal renal function {133}:

Digitalization:
The following total amounts should be divided into three or more doses, with the initial portion representing approximately one half the total, and the remaining doses administered every six to eight hours, with careful assessment of clinical response before each additional dose {133}. If the patient's clinical response requires a change from the calculated loading dose of digoxin, the calculation of the maintenance dose should be based upon the amount actually given {133}.

50 mcg (0.05 mg) per mL (Rx) [Lanoxin Pediatric Elixir (alcohol 11.5%) (tartrazine)]Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F) {01}. Store in a tight container and protect from light {01}.Auxiliary labeling:
• Keep out of reach of children.
• Keep container tightly closed.
• Do not take other medicines without advice from your doctor.

DIGOXIN TABLETS USP

Note: Variability in the bioavailability of digoxin tablets was recognized as a clinical problem in the early 1970s. {66}{67}{68} These differences in bioavailability were reported among different brands of digoxin tablets as well as among different lots of digoxin tablets produced by the same manufacturer. {68} In response to the problems of bio-inequivalence, official dissolution standards were established. {68} Problems have not been reported following establishment of these standards. However, because bioavailability from any digoxin tablet is incomplete (£ 80%), clinicians should consider this as a possible source of the problem when unexplained difficulty is encountered in the digitalization or maintenance therapy of patients with digoxin tablets.
Digoxin tablets are less bioavailable than digoxin injection; switching from the injection to the tablets for maintenance therapy will require a dosage adjustment {01}. The recommended dose of the tablets is 1.25 times the intravenous dose (e.g., a 100-mcg dose of digoxin injection is considered equivalent to a 125-mcg tablet dose) {01}. See Bioequivalence information section.

Usual adult dose
Congestive heart failure

Digitalization:
Rapid digitalization is achieved by administering a loading dose based upon projected peak digoxin body stores (e.g., body stores of 8 to 12 mcg per kg of body weight in patients with heart failure and normal sinus rhythm; 6 to 10 mcg per kg of body weight for patients with renal insufficiency) {01}: Oral, roughly one half the total loading dose given as the first dose, with the remaining portion divided and administered every six to eight hours (e.g., 500 to 750 mcg [0.5 to 0.75 mg] initially, followed by 125 to 375 mcg [0.125 to 0.375 mg] administered every six to eight hours) until an appropriate clinical response is achieved {01}. Before each additional dose is given, the patient's clinical response should be assessed carefully {01}. If the patient's clinical response requires a change from the calculated loading dose of digoxin, calculation of the maintenance dose should be based upon the amount actually given {01}. For a 70-kg patient to achieve 8 to 12 mcg per kg of body weight peak body stores, the usual amount administered is 750 to 1250 mcg (0.75 to 1.25 mg) {01}.

Slow digitalization is achieved by beginning an appropriate maintenance dose (allowing digoxin body stores to accumulate slowly) and will be achieved in approximately five half-lives {01}. Depending upon the patient's renal function, digitalization by this method will take between one and three weeks {01}.

Maintenance:
Digoxin maintenance doses for estimated peak body stores of 10 mcg per kg of body weight generally have ranged from 62.5 to 500 mcg (0.0625 to 0.5 mg), administered orally as one or two doses per day, the dosage titrated according to the patient's age, lean body weight, and renal function {01}. In patients digitalized with a loading dose, the subsequent maintenance dose can be calculated as a percentage of the loading dose {01}. Doses may be increased every two weeks according to clinical response {01}. Therapy is generally initiated at the following doses:

For patients up to 70 years of age—
Oral, 250 mcg (0.25 mg) once a day {01}.

For patients 70 years of age and older or with impaired renal function—
Oral, 125 mcg (0.125 mg) once a day {01}.

For patients with marked impaired renal function—
Oral, 62.5 mcg (0.0625 mg) once a day {01}.

Atrial fibrillation, chronic
Doses should be titrated to the minimum dose that achieves the desired ventricular rate control without causing undesirable side effects {01}.

Usual pediatric dose
Congestive heart failure
Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area {01}. Children older than 10 years of age require adult dosages in proportion to their body weight {01}. Some researchers have suggested that infants and young children tolerate slightly higher serum digoxin concentrations than do adults {01}. For digitalization dosing of infants and children, see Digoxin Elixir USP or Digoxin Injection USP . The following daily maintenance doses are based on average patient response for children with normal renal function {01}. Divided daily dosing is recommended for children up to 10 years of age:

Maintenance:

Children 2 to 5 years of age—
Oral, 10 to 15 mcg (0.01 to 0.015 mg) per kg of body weight {01}.

Children 5 to 10 years of age—
Oral, 7 to 10 mcg (0.007 to 0.01 mg) per kg of body weight {01}.

Children 10 years of age and older—
Oral, 3 to 5 mcg (0.003 to 0.005 mg) per kg of body weight {01}.

250 mcg (0.25 mg) (Rx) [Lanoxin (scored)] [Novo-Digoxin{103}][Generic]{103}Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F) {01}. Store in a tight container and protect from light.Auxiliary labeling:
• Keep out of reach of children.
• Do not take other medicines without advice from your doctor.

Caution:The small, white tablets of digoxin 0.25 mg have been confused by numerous patients with other, similar-looking medications such as furosemide, with resultant serious dosage accidents. To reduce this hazard, the dispenser may:

• check with the prescriber; suggest digoxin capsules be used instead of tablets.
• caution the patient about the potential hazard.
• apply auxiliary ``Heart medicine'' labels to digoxin tablet container.
• use containers of different size or appearance for similar-looking medications.
• suggest that patient not use tablets from both containers at same time.
• suggest that patient never transfer digoxin from original to other containers.
• suggest that patient use separate storage areas for medications that look alike.

Parenteral Dosage FormsDIGOXIN INJECTION USP

Note: It is recommended that digoxin injection be administered intravenously, slowly, over a period of five minutes or longer {134}. Rapid or bolus intravenous administration has been associated with systemic and coronary arteriolar constriction and is not recommended {134}. Intramuscular administration of digoxin injection also is not recommended because it can cause severe pain at the injection site {134}. If digoxin must be administered by the intramuscular route, it should be injected deep into the muscle, followed by massage {134}. No more than 2 mL should be injected into a single site {134}. Digoxin should not be mixed with other medications in the same container or simultaneously administered in the same intravenous line {134}.
For equivalent doses for switching from the intravenous dosage form to the oral capsule, elixir, or tablet dosage forms, see Bioequivalence information section.

Usual adult dose
Congestive heart failure
Rapid digitalization is achieved by administering a loading dose based upon projected peak digoxin body stores (e.g., body stores of 8 to 12 mcg per kg of body weight in patients with heart failure and normal sinus rhythm; 6 to 10 mcg per kg for patients with renal insufficiency) {134}. Roughly one half the total loading dose should be given intravenously as the first dose, with the remaining portion divided and administered every six to eight hours (e.g., 400 to 600 mcg [0.4 to 0.6 mg] initially, followed by 100 to 300 mcg [0.1 to 0.3 mg] administered every six to eight hours) until an appropriate clinical response is achieved {134}. Before each additional dose is given, the patient's clinical response should be assessed carefully {134}. If the patient's clinical response requires a change from the calculated loading dose of digoxin, calculation of the maintenance dose should be based upon the amount actually given {134}. For a 70-kg patient to achieve 8 to 12 mcg per kg of body weight peak body stores, the usual amount administered is 600 to 1000 mcg (0.6 to 1 mg) {134}.

Slow digitalization is achieved by beginning an appropriate maintenance dose (allowing digoxin body stores to accumulate slowly) and will be achieved in approximately five half-lives {134}. Depending upon the patient's renal function, digitalization by this method will take between one and three weeks {134}.

Maintenance:
Digoxin injection maintenance doses required for estimated peak body stores of 10 mcg per kg of body weight generally have ranged from 75 mcg to 350 mcg (0.075 to 0.35 mg), administered once a day, the dose titrated according to the patient's age, lean body weight, and renal function {134}. In patients digitalized with a loading dose, the subsequent maintenance dose can be calculated as a percentage of the loading dose {134}. Doses may be increased every two weeks according to response {134}.

Atrial fibrillation, chronic
Doses should be titrated to the minimum dose that achieves the desired ventricular rate control without causing undesirable side effects {01}.

Usual pediatric dose
Congestive heart failure
In newborns, digoxin renal clearance is decreased (especially in premature infants) and digoxin doses should be adjusted accordingly {132}. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area {132}. Children older than 10 years of age require adult dosages in proportion to their body weight {132}. Some researchers have suggested that infants and young children tolerate slightly higher serum digoxin concentrations than do adults {132}.

Digitalization:
The following total amounts divided into three or more doses, with the initial portion representing approximately one half the total, doses then being administered every four to eight hours, with careful assessment of clinical response before each additional dose {132}. If the patient's clinical response requires a change from the calculated loading dose of digoxin, the calculation of the maintenance dose should be based upon the amount actually given {132}.

250 mcg (0.25 mg) per mL (Rx) [Lanoxin Injection (alcohol 10%)][Generic]{103}Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F) {01}. Protect from freezing and protect from light {01}.Preparation of dosage form:
Digoxin Injection USP may be administered undiluted or may be diluted with a fourfold or greater volume (to reduce the risk of precipitation) of sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection for intravenous administration. {01}Stability:
Do not use if markedly discolored or if a precipitate is present. Immediate use of diluted Digoxin Injection USP is recommended {01}.

Norregaard-Hansen K, Klitgaard NA, Pedersen KE. The significance of the enterohepatic circulation on the metabolism of digoxin in patients with the ability of intestinal conversion of the drug. Acta Med Scand 1986; 220: 89-92.